Mechanisms of Estrogenic Modulation of Adenosinergic Sleep Pressure

项目摘要： 原发性睡眠障碍是最常见的医疗条件之一，临床数据显示，女性 更有可能在一生中经历睡眠障碍。这种增加的风险出现在青春期， 与卵巢类固醇，特别是雌激素的波动有关，这表明性腺类固醇 和生理性别是睡眠中断的重要危险因素。尽管人们对睡眠的了解越来越多， 调节机制，雌激素如何影响睡眠电路知之甚少。历史上，男性 啮齿类动物已经成为阐明控制睡眠的神经回路的基石。可惜这 导致我们对雌激素如何调节女性这些回路的理解存在重大差距。的 雌性啮齿动物提供了探索睡眠回路的机会，以阐明卵巢分泌的机制。 类固醇调节睡眠，因为雌性大鼠的睡眠模式对睡眠的自然波动非常敏感。 卵巢类固醇，如雌二醇（E2）。利用成年雌性Sprague-Dawley大鼠， 了解雌激素对正常清醒和睡眠模式的影响。我们的研究始终 研究表明，当内源性卵巢类固醇或外源性E2 在女性中升高，但在男性中不升高。这种效应是通过抑制睡眠活跃的神经元介导的， 正中视前核（MnPN）。此外，我们已经证明，E2是能够显着抑制 在睡眠剥夺的情况下，当稳态睡眠需求（也称为睡眠压力）增加时， 结合我们以前的发现，这一观察结果表明，E2可能会消除体内平衡的需要， 睡觉用的此外，初步的数据表明，E2减弱腺苷信号的作用，在 促进睡眠的A2 A受体，导致睡眠时间减少。这一发现意义重大，因为腺苷 是一种已知的睡眠压力介质，在MnPN和密切相关的（但非E2） 腹外侧视前核（VLPO）。这些数据表明，E2和E2之间存在相互作用。 以及调节腺苷产生睡眠压力的能力的腺苷。但具体 这种相互作用的机制仍然没有确定。这个项目将测试的假设，雌激素 睡眠压力的调节需要腺苷信号传导功效的衰减。我们将测试这个 通过（1）确定雌二醇是否通过行为和行为两方面降低对睡眠的稳态需求， 腺苷含量、合成和清除的实验和分子测定，以及（2）确定是否 雌二醇通过抑制MnPN神经元的细胞作用， 通过受体药理学和神经元活动的实验，研究腺苷在睡眠回路中的作用。 了解E2和腺苷的相互作用可以阐明激素含量和睡眠之间的联系， 为考虑女性性别和荷尔蒙状态的睡眠障碍治疗提供机会。

Project Summary: Primary sleep disorders are among the most common medical conditions, and clinical data show women are far more likely to experience sleep disorders over their lifespan. This increased risk emerges at puberty and has been associated with fluctuations in ovarian steroids, particularly estrogens, suggesting that gonadal steroids and biological sex are significant risk factors for sleep disruptions. Despite a growing understanding of sleep regulatory mechanisms, how estrogens influence the sleep circuitry is poorly understood. Historically, male rodents have served as the cornerstone for elucidating the neural circuitries governing sleep. Unfortunately, this has resulted in a significant gap in our understanding of how estrogens modulate these circuits in females. The female rodent offers the opportunity to probe the sleep circuitry to elucidate the mechanisms by which ovarian steroids modulate sleep, as sleep patterns in the female rat are exquisitely sensitive to natural fluctuations in ovarian steroids such as estradiol (E2). Using adult female Sprague-Dawley rats, our group has made inroads into understanding estrogenic influences over normal wake and sleep patterns. Our studies consistently demonstrate that sleep time is significantly reduced when endogenous ovarian steroids or exogenous E2 are elevated in females but not males. This effect is mediated through the inhibition of sleep-active neurons in the median preoptic nucleus (MnPN). Moreover, we have demonstrated that E2 is capable of marked suppression of sleep under sleep deprivation, when homeostatic sleep need, also known as sleep pressure, is increased. Taken together with our previous findings, this observation suggests that E2 may dissipate the homeostatic need for sleep. Furthermore, preliminary data suggest that E2 attenuates the action of adenosine signaling at the sleep-promoting A2A receptor, resulting in reduced sleep duration. This finding is significant because adenosine is a known mediator of sleep pressure, with established actions at the MnPN and a closely related (but non-E2 sensitive) nucleus, the ventral lateral preoptic (VLPO). These data suggest that there is an interplay between E2 and adenosine which modulates the ability of adenosine to generate sleep pressure. However, the specific mechanism for this interplay remains undetermined. This project will test the hypothesis that estrogenic modulation of sleep pressure requires the attenuation of adenosine signaling efficacy. We will test this hypothesis by (1) determining if estradiol reduces the homeostatic need for sleep through both behavioral experiments and molecular assays of adenosine content, synthesis, and clearance, and (2) determining if estradiol attenuates neuronal activity of sleep active MnPN neurons, through inhibiting the cellular action of adenosine in the sleep circuitry, through experiments in both receptor pharmacology and neuronal activity. Understanding interactions of E2 and adenosine may illuminate ties between hormonal content and sleep, and provide opportunities for sleep disorder treatments that take female sex and hormonal state into account.